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Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Folate Receptor–Targeted Polymeric Micellar Nanocarriers for Delivery of Orlistat as a Repurposed Drug against Triple-Negative Breast Cancer

Ramasamy Paulmurugan, Rohith Bhethanabotla, Kaushik Mishra, Rammohan Devulapally, Kira Foygel, Thillai V. Sekar, Jeyarama S. Ananta, Tarik F. Massoud and Abraham Joy
Ramasamy Paulmurugan
1Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
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  • For correspondence: paulmur8@stanford.edu
Rohith Bhethanabotla
1Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
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Kaushik Mishra
2Department of Polymer Science, University of Akron, Akron, Ohio.
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Rammohan Devulapally
1Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
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Kira Foygel
1Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
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Thillai V. Sekar
1Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
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Jeyarama S. Ananta
1Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
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Tarik F. Massoud
1Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
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Abraham Joy
2Department of Polymer Science, University of Akron, Akron, Ohio.
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DOI: 10.1158/1535-7163.MCT-15-0579 Published February 2016
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Abstract

Triple-negative breast cancer (TNBC) is a recalcitrant malignancy with no available targeted therapy. Off-target effects and poor bioavailability of the FDA-approved antiobesity drug orlistat hinder its clinical translation as a repurposed new drug against TNBC. Here, we demonstrate a newly engineered drug formulation for packaging orlistat tailored to TNBC treatment. We synthesized TNBC-specific folate receptor–targeted micellar nanoparticles (NP) carrying orlistat, which improved the solubility (70–80 μg/mL) of this water-insoluble drug. The targeted NPs also improved the delivery and bioavailability of orlistat to MDA-MB-231 cells in culture and to tumor xenografts in a nude mouse model. We prepared HEA–EHA copolymer micellar NPs by copolymerization of 2-hydroxyethylacrylate (HEA) and 2-ethylhexylacrylate (EHA), and functionalized them with folic acid and an imaging dye. Fluorescence-activated cell sorting (FACS) analysis of TNBC cells indicated a dose-dependent increase in apoptotic populations in cells treated with free orlistat, orlistat NPs, and folate-receptor–targeted Fol-HEA-EHA-orlistat NPs in which Fol-HEA-EHA-orlistat NPs showed significantly higher cytotoxicity than free orlistat. In vitro analysis data demonstrated significant apoptosis at nanomolar concentrations in cells activated through caspase-3 and PARP inhibition. In vivo analysis demonstrated significant antitumor effects in living mice after targeted treatment of tumors, and confirmed by fluorescence imaging. Moreover, folate receptor–targeted Fol-DyLight747-orlistat NP–treated mice exhibited significantly higher reduction in tumor volume compared to control group. Taken together, these results indicate that orlistat packaged in HEA-b-EHA micellar NPs is a highly promising new drug formulation for TNBC therapy. Mol Cancer Ther; 15(2); 221–31. ©2015 AACR.

This article is featured in Highlights of This Issue, p. 219

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received July 16, 2015.
  • Revision received October 30, 2015.
  • Accepted November 2, 2015.
  • ©2015 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 15 (2)
February 2016
Volume 15, Issue 2
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Folate Receptor–Targeted Polymeric Micellar Nanocarriers for Delivery of Orlistat as a Repurposed Drug against Triple-Negative Breast Cancer
Ramasamy Paulmurugan, Rohith Bhethanabotla, Kaushik Mishra, Rammohan Devulapally, Kira Foygel, Thillai V. Sekar, Jeyarama S. Ananta, Tarik F. Massoud and Abraham Joy
Mol Cancer Ther February 1 2016 (15) (2) 221-231; DOI: 10.1158/1535-7163.MCT-15-0579

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Folate Receptor–Targeted Polymeric Micellar Nanocarriers for Delivery of Orlistat as a Repurposed Drug against Triple-Negative Breast Cancer
Ramasamy Paulmurugan, Rohith Bhethanabotla, Kaushik Mishra, Rammohan Devulapally, Kira Foygel, Thillai V. Sekar, Jeyarama S. Ananta, Tarik F. Massoud and Abraham Joy
Mol Cancer Ther February 1 2016 (15) (2) 221-231; DOI: 10.1158/1535-7163.MCT-15-0579
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